Codamine

Uses

Diphenhydramine is used for the treatment of followings:

• Seasonal, perennial, vasomotor rhinitis
• Urticaria, angioneurotic oedema, anaphylaxis
• Pruiritic conditions
• Premedication for emesis and motion sickness
• Miscellaneous like meniere's disease and parkinsonism

Pholcodine is used for a cough suppressant for the temporary relief of non-productive dry cough. It is stated to present a required label indication of "temporary relief of dry cough". Cough is the respiratory movement that occurs after an irritation signal is transmitted to the central nervous system and further stimulates the medulla oblongata. This stimulation causes a motor output that is sent through motoneurons to the respiratory muscles. A non-productive cough is a type of cough characterized by the absence of sputum, and it has a large inspiration that will cause continuous coughing.

Codamine is also used to associated treatment for these conditions: Allergic Rhinitis (AR), Allergic cough, Allergies, Anaphylaxis, Angioedema, Common Cold, Common Cold/Flu, Conjunctival irritation, Cough, Cough Variant Asthma, Cough caused by Common Cold, Eye allergy, Fever, Insect Bites, Insect Stings, Insomnia, Irritative cough, Itching of the nose, Itching of the throat, Motion Sickness, Nasal Congestion, Oral Mucositis, Pain, Parkinsonian Syndromes, Pollen Allergy, Productive cough, Pruritus, Rash, Rhinorrhoea, Sinus Congestion, Sinus headache, Skin Irritation, Sneezing, Sunburn, Symptoms of Acute Bronchitis Accompanied by Coughing, Upper respiratory tract hypersensitivity reaction, site unspecified, Urticaria, Dermatographism, Dry cough, Watery itchy eyes, Airway secretion clearance therapy, ExpectorantCough, Cough caused by Common Cold, Flu Like Symptom, Flu caused by Influenza, Irritative cough, Rhinorrhoea, Sinusitis, Sneezing, Throat irritation, Dry cough, Watery eyes

How Codamine works

Diphenhydramine predominantly works via the antagonism of H1 (Histamine 1) receptors . Such H1 receptors are located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons . When the H1 receptor is stimulated in these tissues it produces a variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and the GIT, and eosinophilic chemotaxis that promotes the allergic immune response .

Ultimately, diphenhydramine functions as an inverse agonist at H1 receptors, and subsequently reverses effects of histamine on capillaries, reducing allergic reaction symptoms . Moreover, since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center .

Furthermore, H1 receptors are similar to muscarinic receptors . Consequently, diphenhydramine also acts as an antimuscarinic . It does so by behaving as a competitive antagonist of muscarinic acetylcholine receptors, resulting in its use as an antiparkinson medication .

Lastly, diphenhydramine has also demonstrated activity as an intracellular sodium channel blocker, resulting in possible local anesthetic properties .

The mechanism of action of pholcodine is directly performed in the medulla oblongata. In this site, it exerts analgesic properties on the peripheric reflexogenic receptors. This site is commonly known as the "cough center."

Dosage

Codamine dosage

Adult-

• Most allergic conditions: 25-50 mg three times a day with a further 50 mg at night.

Children-

• 1 to 5 years of age: 5 mg i.e., 2.5 ml of elixir 4 times a day
• More than 6 years of age: 10 mg i.e. 5 ml of elixir 4 times a day

Adult:

• Symptomatic relief of non-productive cough: 5-10 mg 3-4 times daily.

Child:

• 12-18 year: 5-10 mg 3-4 times daily.
• 6-12 year: 2-5 mg 3-4 times daily.
• Children under the age of 6 year:Not to be used

Side Effects

Side effect includes sedation, dizziness, tinnitus, fatigue, ataxia, blurred vision, diplopia, euphoria, and epigastric discomfort.

Dizziness, occasional drowsiness, nausea, vomiting, constipation, rash, sputum retention, excitation, confusion, ataxia.

Toxicity

Overdose is expected to result in effects similar to the adverse effects that are ordinarily associated with the use of diphenhydramine, including drowsiness, hyperpyrexia, and anticholinergic effects, among others . Additional symptoms during overdose may include mydriasis, fever, flushing, agitation, tremor, dystonic reactions, hallucinations and ECG changes . Large overdose may cause rhabdomyolysis, convulsions, delirium, toxic psychosis, arrhythmias, coma and cardiovascular collapse . Moreover, with higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse may follow .

Although diphenhydramine has been in widespread use for many years without ill consequence, it is known to cross the placenta and has been detected in breast milk . This medication should therefore only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing fetus or suckling infant .

Pharmacokinetic studies indicate no major differences in the distribution or elimination of diphenhydramine compared to younger adults . Nevertheless, diphenhydramine should be used with caution in the elderly, who are more likely to experience adverse effects . Avoid use in elderly patients with confusion .

The results of a review on the use of diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on Glomerular filtration rate (GFR) .

After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease . However, the mean plasma clearance and apparent volume of distribution were not significantly affected .

LD₅₀=500 mg/kg (orally in rats). Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death.

Generally, pholcodine is significantly less toxic than codeine. Nonetheless, it is important to consider the significant depressive respiratory effect.

Precaution

Caution should be exercised with patients in whom drowsiness is undesirable e.g., drivers, machine operators. Concomitant consumption of alcohol or central nervous system (CNS) depressants will potentiate drowsiness.

Renal and/or hepatic impairment. Caution in patients with impaired respiratory function and asthma. May cause occasional drowsiness, caution when driving or operating machinery. Pregnancy and lactation.

Interaction

Diphenhydramine administration significantly reduces the absorption of the antituberculous agent para-aminosalicyclic acid (PAS) from the gastrointestinal tract. CNS depressants may potentiate the sedative action of Diphenhydramine. Anticholinergic drugs may potentiate Diphenhydramine’s anticholinergic side effects.

Not to be used with MAOI or within 14 days of stopping treatment. May enhance sedative effect of alcohol and other CNS depressants e.g. sedatives, hypnotics, barbiturates, narcotic analgesics, phenothiazines, tricyclic antidepressants. Hypotensive effect may be enhanced when used with antihypertensive agents and diuretics. Interaction with neuromuscular blocking agent has been reported.

Volume of Distribution

Diphenhydramine is widely distributed throughout the body, including the CNS . Following a 50 mg oral dose of diphenhydramine, the volume of distribution is in the range of 3.3 - 6.8 l/kg .

The reported volume of distribution depends on the pharmacokinetic model and it can be of 265L based on a one-compartment model to 3207L in a two-compartment model.

Elimination Route

Diphenhydramine is quickly absorbed after oral administration with maximum activity occurring in approximately one hour . The oral bioavailability of diphenhydramine has been documented in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration .

After oral administration of 60 mg of pholcodine, the Tmax and Cmax are reported to be 1.3 hours and 26.3 ng/ml. In the same administration, the AUC in plasma and saliva are reported to be 1.67 and 6.61 mg h/l respectively. The absorption of pholcodine is reported to represent approximately 88% of the administered dose.

Half Life

The elimination half-life ranges from 2.4-9.3 hours in healthy adults . The terminal elimination half-life is prolonged in liver cirrhosis .

After oral administration of 60 mg of pholcodine, the half-life in plasma, saliva and urine are 45, 55 and 45 hours respectively.

Clearance

Values for plasma clearance of a 50 mg oral dose of diphenhydramine has been documented as lying in the range of 600-1300 ml/min .

After oral administration of 60 mg of pholcodine, the clearance rate was reported to be 126 ml/min.

Elimination Route

The metabolites of diphenhydramine are conjugated with glycine and glutamine and excreted in urine . Only about 1% of a single dose is excreted unchanged in urine . The medication is ultimately eliminated by the kidneys slowly, mainly as inactive metabolites .

After oral administration of pholcodine, the serum concentration peaks and declines in a monoexponential manner. The percent of the dose excreted unchanged is of approximately 25-30%. Part of the administered dose is composed by metabolites that can be recovered in urine. From the administered dose, the fecal excretion corresponds to the 5% of the administered dose as unchanged pholcodine.

Pregnancy & Breastfeeding use

Category B: There are no adequate and well controlled studies in pregnant women using diphenhydramine hydrochloride. Therefore, diphenhydramine hydrochloride should be used in pregnancy only if clearly needed. Diphenhydramine hydrochloride has been reported to be excreted in breast milk and thus, use of diphenhydramine hydrochloride in lactating mother is not recommended.

Category not classified

Contraindication

Known hypersensitivity to Diphenhydramine Hydrochloride, Ammonium chloride is contra-indicated in presence of impaired hepatic or renal function.

Patients in, or at risk of developing respiratory failure. Chronic bronchitis, COPD, bronchiolitis, and bronchiectasis due to sputum retention. Concurrent or recent use (within preedicing 14 days) of MAOIs. Children <6 yr

Acute Overdose

Symptoms: Impaired consciousness; psychosis, seizures, antimuscarinic symptoms (e.g. mydriasis, tachycardia, tachyarrhythmias), resp failure, rhabdomyolysis; acute delirium with visual and auditory hallucination (topical).

Management: Supportive and symptomatic treatment. Convulsions and marked CNS stimulation may be treated with IV diazepam.

Symptoms: Drowsiness, nausea, restlessness, excitement, ataxia and respiratory depression.

Management: Provide symptomatic and supportive treatment. Maintain respiration; may use activated charcoal or gastric lavage to remove the ingested Pholcodine. In cases of severe overdosage, naloxone may be given to reverse the central and peripheral opioid effects.

Storage Condition

Store between 15-30° C. Protect from moisture.

Store below 25° C.

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